Stillbirth (intrauterine fetal demise, fetal death in utero)

1. What every clinician should know

Epidemiology

Stillbirth (fetal demise beyond 20 weeks gestation) occurs at an overall rate of 6.2 per 1,000 births in the United States. The rate of fetal death between 20-27 weeks’ gestation has remained stable at 3.2 per 1,000 births, while the rate of fetal death beyond 28 weeks’ gestation has decreased slightly from 4.3 to 3.0 per 1,000 births since the 1990s.

Risk factors

Several risk factors have been identified as placing a woman at a higher risk of stillbirth:

multiple gestations and the use of assisted reproductive technologies (ART)

tobacco and drug use

maternal obesity

medical co-morbidities

In the U.S., there remains a significant racial disparity in the rate of stillbirth, with non-Hispanic black women experiencing stillbirth at a rate of 11.13 vs. 4.79 per 1,000 live births and fetal deaths as compared to non-Hispanic white women, respectively. Hispanic women are also at a higher risk of stillbirth as compared to non-Hispanic white women (5.44 per 1,000 live births and fetal deaths). Although the root of this disparity is undoubtedly multifactorial, a majority of the increase in fetal death is thought to be due to infectious etiologies and obstetric complications.

Extremes of maternal age are also significant risk factors for stillbirth. Compared to 25-29 year old women, 15-19 year old women experience stillbirth at a 38% higher rate. The risk of stillbirth at term also increases with advancing maternal age, with a relative risk (RR) of 1.32 (95% confidence interval [CI] 1.22, 1.43) for 35-39 year olds, and 1.88 (95% CI 1.64, 2.16) for those older than 40.

In recent years, the use of ART has increased, resulting in an increase in the rate of multiple gestations. The stillbirth rate for twins is 2.7-fold higher than singletons, and 4.6-fold higher for triplet and higher-order pregnancies. Part of the risk is attributable to higher rates of preterm birth, fetal growth restriction and maternal medical complications (hypertension, gestational diabetes) seen in pregnancies with multiple gestations.

It also appears that the use of ART itself is a risk factor for stillbirth, with singleton pregnancies conceived as a result of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) having an odds ratio (OR) for stillbirth of 4.44 (95% CI 2.38, 8.28) compared with spontaneously conceived singleton pregnancies. Furthermore, couples taking 1 year or more to conceive and women who conceived after non-IVF ART had a stillbirth risk similar to that of fertile couples but significantly lower than women pregnant after IVF/ICSI. These findings indicate that the increased stillbirth risk may be a result of the IVF/ICSI and not the underlying infertility itself.

A history of previous stillbirth, as well as a prior birth of a growth restricted fetus before 32 weeks, are also associated with an increased risk of stillbirth in the current pregnancy. A history of stillbirth conferrs a 10-fold increased risk for early fetal demise (20-28 weeks), 2.5-fold for fetal demise after 29 weeks, 4-fold increased risk for antepartum and 12-fold increased risk for intrapartum stillbirth in the subsequent pregnancy.

Modifiable risk factors for stillbirth include obesity and tobacco use. Approximately 1 in 3 of reproductive age women are obese, with BMI greater than 30 kg/m2, which confers an OR of stillbirth of 2.07 (95% CI 1.59, 2.74). It also appears that weight gain between pregnancies increases the risk of fetal demise. Although the etiology for this increase in risk is not well understood, inflammation and vascular/metabolic changes have been proposed as potential mechanisms. Tobacco use is associated with a 36% increased odds of stillbirth; however, women who quit smoking reduce their risk of stillbirth to the same level as nonsmokers, and smoking cessation should be strongly encouraged.

Pathogenesis

Pathogenesis of stillbirth is multifactorial, with infection and maternal medical complications significant causes. Up to 20% of stillbirths are believed to be associated with infection, either due to direct fetal infection or severe maternal illness. Infection with Treponema pallidum can result in up to a 50% fetal death rate in utero. Other pathogens implicated in stillbirth include Escherichia coli, group B Streptococci, Mycoplasma hominis, Ureaplasma, Gardnerella and Bacteroides spp. Toxoplasma gondii, leptospirosis and Listeria monocytogenes are less common. Viral infections, such as parvovirus and cytomegalovirus (CMV) have also been associated with fetal demise.

Many maternal medical conditions are associated with elevated risk of stillbirth:

diabetes

hypertension

renal disease

systemic lupus erythematosus

intrahepatic cholestasis of pregnancy

acquired thrombophilias

alloimmunization

Patients with diabetes are at a higher risk of stillbirth, particularly if poor glycemic control is present. These pregnancies are at high risk of congenital anomalies, abnormalities in fetal growth and abnormal labor progression. Maternal hyperglycemia triggers increased insulin production in the fetus to control the ensuing fetal hyperglycemia. Insulin, in turn, stimulates fetal growth, which if excessive can result in metabolic acidosis due to placental insufficiency. Multiple studies report poor maternal glycemic control as a finding in women with stillbirth, with overall increased risk of 2.5-5-fold compared to non-diabetic parturients.

Pregnancies complicated by isolated chronic hypertension have similar rates of stillbirth as the general population. However, the risk of fetal demise increases with the severity of the disease, with the highest perinatal mortality reported in women with chronic hypertension with superimposed preeclampsia.

There is a linear relationship between the risk of stillbirth and the severity of renal disease. The rate of stillbirth (36%) is highest for women with creatinine greater than 2.4 mg/dL. Patients who require hemodialysis during pregnancy are at particular high risk of stillbirth, with live birth rate of 52%. The risk of preeclampsia in this patient population is 50% and increases to 80% if chronic hypertension also is present.

Systemic lupus erythematosus (SLE) carries an elevated stillbirth rate of 40-150 per 1,000 births. Maternal disease activity dictates fetal prognosis, with worse outcomes if lupus nephritis is present. Women who have autoantibodies to SSA and SSB are at risk of fetal congenital heart block, which can lead to stillbirth. This occurs due to transplacental passage of these antibodies, causing fibrosis and destruction of the atrioventricular conduction system. If fetal hydrops develops as a result of fetal heart block, the risk of stillbirth is 1 in 3. Up to 30% of SLE patients also have antiphospholipid antibodies that are associated with elevated risk of fetal demise after 10 weeks of gestation.

Intrahepatic cholestasis of pregnancy is characterized by elevation in serum bile acids and pruritus. Stillbirth is rare prior to third trimester, occurring at a rate of 12-30/1,000 later in gestation. Antenatal testing does not reliably predict fetal well-being and the mechanism behind the higher rates of stillbirth in this condition are not well understood.

Acquired thrombophilias have also been reported to have an increased risk of stillbirth. Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies, obstetric complications (recurrent spontaneous losses before 10 weeks, severe preeclampsia or evidence of placental insufficiency resulting in preterm delivery before 34 weeks or one fetal demise after 10 weeks gestation) and thrombotic events. Antibodies include lupus anticoagulant, anticardiolipin antibodies (IgM and IgG), and anti-beta2-glycoprotein I IgM and IgG. Patients found to have these antibodies in high titers (99th percentile) appear to have an elevated risk of stillbirth, although the extent of this risk is unknown.

The data on the risk of stillbirth in women with inherited thrombophilias is conflicting; retrospective studies as well as a meta-analysis have reported an increased stillbirth risk associated with the factor V Leiden mutation, G20210A prothrombin mutation, and antithrombin III and protein S deficiencies. However, prospective studies, including a cohort of over 4,000 healthy American women, failed to show an association of FVL or G20210A mutations with pregnancy loss, preeclampsia or fetal growth restriction. The common pathway proposed to explain the possible link of stillbirth with thrombophilias is placental thrombosis, infarction and inflammation. The American Congress of Obstetricians and Gynecologists (ACOG) does not recommend testing for inherited thrombophilias in patients with obstetric complications in the absence of personal or family history of thrombotic event.

Alloimmunization (red cell or platelet), although rare, is associated with a risk of stillbirth. With introduction of anti-Rhesus (RhD) immune globulin, RhD alloimmunization in pregnancy has decreased significantly, such that alloimmunization is often due to other antibodies, such as those directed against the Kell antigen. Fetal platelet alloimmunization results in fetal alloimmune thrombocytopenia due to passage of maternal antibodies through the placenta and subsequent destruction of fetal platelets due to antigens inherited from the father. Most common antigens implicated in fetal thrombocytopenia include HPA-1a and HPA-5 in Caucasians. With severe disease (platelets less than 50 x 109/L), intracranial hemorrhage and stillbirth can occur.

Chromosomal abnormalities account for up to 13% of all stillbirths, and are even more common in malformed fetuses.

When stillbirth is related to cytogenetic abnormalities, the proportion related to specific aneuploidies is as follows:

Trisomy 21 31%

Monosomy X 22%

Trisomy 18 22%

Trisomy 13 6%

other chromosomal abnormalities 19%

In instances when fetal karyotype is normal and the abnormal cell line is present only in the placenta, a confined placental mosaicism occurs. This is found in about 1% of chorionic villi samples. In such a circumstance, stillbirth and growth restriction occur in up to 20% of affected pregnancies.

Fetomaternal hemorrhage is the cause of stillbirth in about 4% of cases. Loss of more than 25% of fetal blood volume has been associated with rates of stillbirth as high as 26%. Fetomaternal hemorrhage usually occurs as a result of abruption and abdominal trauma. Given this, patients diagnosed with stillbirth should be evaluated for fetomaternal hemorrhage prior to delivery.

Placental and umbilical cord causes of stillbirth include:

placental abruption

placenta previa

vasa previa

cord prolapse

cord torsion

cord occlusion

Placental abruption is a clinical diagnosis with signs including vaginal bleeding, abdominal pain and abnormal fetal heart rate tracing. Risk factors include trauma, drug use, hypertension and preterm premature rupture of membranes. Histologic evaluation of the placenta is not always helpful given the clinical nature of the diagnosis; however, infarction, thrombosis, and hemosiderin deposits consistent with chronic abruption may be present.

Vasa previa can result in significant fetal blood loss and even exsanguination due to rupture of fetal vessels coursing through the membranes.

Umbilical cord abnormalities may account for up to 15% of stillbirths. Cord prolapse can result in stillbirth and is an obstetric emergency. Cord occlusion can cause fetal death by disturbance of blood flow to the fetus. This can occur due to cord entanglement (nuchal cords, true knots, or cord entanglement seen in monochorionic, monoamniotic gestations), or thrombosis of vessels coursing in the cord. It should be noted, however, that an isolated presence of a true knot or a nuchal cord should not be taken as evidence of cord accident, unless histopathologic findings are consistent (edema, congestion, thrombosis in acute cases, and grooving and constriction of umbilical vessels in persistent cases).

The risk of stillbirth is higher in multiple gestations, largely due to the placental abnormalities, especially in the monochorionic pregnancies. Twin-twin transfusion syndrome occurs in about 10% of monochorionic gestations due to arterio-venous anastomoses. If untreated, the risk of stillbirth is very high. Cord entanglement, as described previously, can be a significant contributor to stillbirth in monochorionic, monoamniotic twins.

Intrapartum stillbirth occurs in about 1 in 1,000 births in the United States. Approximately 10% of these are due to cervical insufficiency and preterm labor, abruption, chorioamnionitis or preterm premature rupture of membranes at previable gestation. The rest are due to obstetric intrapartum events such as cord prolapse, shoulder dystocia or severe birth trauma.

2. Diagnosis and differential diagnosis

A thorough evaluation will result in determination of a possible or probable cause of death in 76.2% of stillbirths.

Most common causes include:

obstetric conditions – 29.3%

placental abnormalities – 23.6%

genetic or structural abnormalities – 13.7%

infection – 12.9%

umbilical cord abnormalities – 10.4%

hypertensive disorders – 9.2%

other maternal medical conditions – 7.8%

A detailed medical and obstetric history as well as assessment of maternal symptoms and circumstances surrounding fetal demise (if known) will help guide work up and suggest possible risk factors for causes of stillbirth. Fetal autopsy should be offered to the patient and is the most useful diagnostic test in determining the cause of stillbirth. If the patient is uncomfortable with a complete autopsy, limited gross examination and/or imaging modalities such as ultrasound and MRI can be helpful.

Evaluation of placenta and the umbilical cord also are important and may propose etiologies of stillbirth such as abruption, vasa previa or umbilical cord vessel thrombosis. Gross description and histologic evaluation should be undertaken and may reveal evidence of infection, genetic abnormalities or thrombosis.

A genetic abnormality may be the cause of stillbirth in up to 13% of all stillbirths, and up to 20% in fetuses with major structural malformations. Parental pedigree, including prior stillbirths and recurrent pregnancy losses should be constructed. Highest yield for tissue culture is from amniocytes, and amniocentesis should be offered prior to delivery. Alternatives for cytologic specimens include an umbilical cord segment, costochondral or patellar tissue, or a placental biopsy below the cord insertion that includes the chorionic plate. Microarray testing also should be offered. Patients should be counseled beforehand on the possibility of copy number variants of unknown significance, mosaicism, and balanced translocations and other genetic abnormalities that may or may not be detected by this test.

Antiphospholipid antibody testing is recommended in cases of stillbirth, especially if complicated by growth restriction, severe preeclampsia or other evidence of placental insufficiency. Evaluation for lupus anticoagulant, anticardiolipin IgM and IgG as well as anti-beta2-glycoprotein I IgM and IgG is indicated. A positive lupus anticoagulant or anticoardiolipid/anti-beta2 antibody titers greater than 99th percentile, confirmed by repeat testing in 12 weeks, are consistent with antiphospholipid syndrome when prior poor obstetric outcome exists.

Fetomaternal hemorrhage evaluation should be performed prior to labor and delivery. This can be assessed with Kleihauer-Betke test or with flow cytometry. Other tests should be guided by clinical situation and patient presentation and may include: urine toxicology screen, parvovirus and syphilis serologies, maternal antibody screen to evaluate for alloimmunization, diabetes evaluation, thyroid function tests and testing for heritable thrombophilias if personal or family history is suggestive.

The yield of several tests for stillbirth evaluation are as follows:

placental pathology – 52.3%

fetal autopsy – 31.4%

fetal karyotype – 9%

anticardiolipin antibodies – 4.8%

fetomaternal hemorrhage screen – 4.6%

maternal antibody screen for alloimmunization – 3.6%

lupus anticoagulant – 3.2%

hemoglobin A1C and/or fructosamine – 2.9%

parvovirus serology – 2%

syphilis screen – 0.4%

Given the low yield of serologic testing for toxoplasmosis, rubella, CMV and herpes simplex (TORCH) titers, routine testing is not recommended and should be guided by the clinical scenario.

3. Management

Antepartum

Once a fetal demise has been diagnosed, timing and route of delivery should be dictated by gestational age, pertinent clinical circumstances, and most importantly, patient preferences. Expectant management or immediate delivery may be undertaken as chosen by the patient. Some women may find it emotionally difficult to make a decision at the time of diagnosis, and there is no urgency to delivery. The risks of infection and coagulopathy are low with expectant management, and the majority of women will enter spontaneous labor within the first two weeks of fetal demise.

If expectant management is elected, frequent assessments are recommended, with close monitoring for clinical signs of infection, bleeding and abdominal pain. Serial laboratory evaluations are of uncertain utility and should be guided by clinical situation.

Patients electing expectant management should also be counseled that the delay in delivery may limit the amount of information that can be obtained from postmortem examination of the infant. Amniocentesis should be offered as cultured amniocytes have the highest yield for genetic assessment of the fetus.

Intrapartum

For fetal demise diagnosed up to 23 weeks, dilation and evacuation (D&E) as well as induction of labor are viable options; D&E, however, has been associated with lower rate of complications and is more cost-effective. If an experienced provider is available, D&E should be offered to patients meeting the gestational age criteria.

If induction of labor is elected, misoprostol is the preferred method of induction at less than 28 weeks gestation, with high-dose oxytocin a valid alternative. For inductions after 28 weeks, standard obstetric protocols should be followed, with the use of oxytocin and prostaglandins as appropriate.

A difficult decision may arise when a woman has a prior uterine scar and fetal demise. If the scar is from previous low transverse incision and fetal gestational age is at less than 28 weeks, induction with misoprostol may be undertaken. After 28 weeks, oxytocin and mechanical ripening with Foley balloon can be considered. Ideally, cesarean delivery should be avoided and should be reserved for maternal indications only.

These patients need to be counseled on the risks of uterine rupture associated with the induction of labor, as well as the risks of undergoing a cesarean delivery and implications for their future child-bearing; after thorough discussion, some may still elect to undergo a repeat cesarean delivery. In a situation where prior classical uterine incision is present, repeat cesarean delivery may be appropriate given the high risk of uterine rupture associated with labor (up to 12%).

Postpartum

Providers should offer emotional support and bereavement services to the patient and family. Close surveillance is warranted for development of depression. Patients should be encouraged to seek preconception counseling regarding subsequent pregnancies.

4. Complications

Intrauterine infection and consumptive coagulopathy can occur in up to 4% of women managed expectantly after the diagnosis of fetal demise. This risk is increased if abruption is suspected, but generally is rare within the first 4 weeks after the diagnosis.

5. Prognosis and outcome

There are currently no screening tests for the development of stillbirth. Risk factors such as maternal medical conditions, BMI, race, age and certain biochemical markers have a low positive predictive value.

Prevention of stillbirth in subsequent pregnancies should focus on modifying risk factors through treatment of maternal medical conditions, attaining an optimal pre-pregnancy weight, and drug, alcohol and smoking cessation if applicable. Preconception counseling is highly encouraged. A thorough history detailing the circumstances of prior fetal demise should be obtained including: gestational age at the time of death, medical co-morbidities, pregnancy complications, and pathology and other stillbirth evaluation results if available.

Low-dose aspirin has been evaluated for prevention of preeclampsia and research is necessary to determine if it may decrease the risk of stillbirth in a subsequent pregnancy. Aspirin decreases the production of potent vasoconstrictor thromboxane A2 by inhibiting platelet cyclo-oxygenase; this potentially may affect utero-placental circulation and decrease placental infarction and insufficiency, which can result in fetal demise.

After pregnancy is confirmed, first trimester screening with biomarker assessment and second trimester msAFP evaluation may be performed. Doppler studies of the uterine artery can be considered. Serial growth ultrasounds and fetal kick counts should be started at 28 weeks gestation, with initiation of antepartum testing at 32 weeks or 1-2 weeks earlier than the gestational age at the time of previous stillbirth. If antepartum testing is initiated earlier than 32 weeks, the plan of action should be discussed with the patient in case non-reassuring fetal status is diagnosed, and prior consultation with neonatologist will be helpful for the family if preterm delivery is planned.

If the pregnancy is uncomplicated, induction of labor can be scheduled for 39 weeks gestation. Amniocentesis for fetal lung maturity assessment should be performed if the delivery is planned for earlier gestational age in the absence of other medical or obstetric indications.

Uterine artery Doppler assessment has been evaluated for early prediction of placental insufficiency. The likelihood of stillbirth is 2.4-fold higher if abnormal Doppler result is present at 22-24 weeks’ gestation. Sensitivity of uterine artery Doppler assessment varies by gestational age due to the heterogeneity of the stillbirth risk at different gestational ages (i.e. fetal death due to placental causes is more likely to occur earlier in gestation), and was 58% and 7%, respectively, for prediction of stillbirth before and after 32 weeks (at a 5% false positive rate).

Pregnancy-associated plasma protein A (PAPP-A) is part of the first trimester analyte assessment and levels below 5th percentile are associated with 9-fold increased risk of stillbirth from all causes, and 46-fold increased risk of stillbirth due to placental dysfunction. Despite what appears to be a significant increase in risk, the positive predictive value is low (1.8%). Maternal serum alpha-fetoprotein (msAFP) assessed in the second trimester with levels greater than 2.5 multiples of the median (MoM) is associated with stillbirth (in the absence of neural or ventral wall defects). If both of these markers are abnormal, there is an additive increase in stillbirth risk.

6. What is the evidence for specific management and treatment recommendations

(In this comprehensive publication from the American Congress of Obstetricians and Gynecologists, specific risk factors, evaluation and management and clinical considerations in cases of stillbirth are discussed.)

(In this manuscript, the authors evaluated the contribution of several diagnostic tests for determining the cause of stillbirth in a prospective, multicenter cohort of patients in the Netherlands. Based on the results of nonselective diagnostic testing, the proposed tiered sequential investigation for intrauterine fetal deaths identifies highest yield tests, with recommendation for subsequent sequential testing guided by clinical circumstances. Postmortem fetal autopsy and placental examination, as well as cytogenetic testing and Kleihauer-Betke evaluation for fetomaternal hemorrhage, are the basic tests recommended for work up of all stillbirths. Routine testing for infections and thrombophilias is not recommended, and evaluation for maternal medical conditions should be guided by clinical presentation.)

(The Stillbirth Collaborative Research Network was created to conduct a multisite population-based case-control study of stillbirth, with patients being enrolled at the time of delivery. The study was designed to provide access to at least 90% of all stillbirths and 90% of all live births for residents within the study enrollment area. The authors identified multiple risk factors associated with stillbirth that would have been known at the time of pregnancy. Although factors such as history of stillbirth, non-Hispanic black race, obesity and maternal age were associated with stillbirth in multivariable analyses, these factors contributed little to explain the variance of stillbirth.)

(In this large U.S. population based study, 512 stillbirths underwent a complete evaluation leading to a cause of death being determined in the majority of stillbirths: obstetric conditions, placental abnormalities, genetic or structural abnormalities, infection, umbilical cord abnormalities, hypertensive disorders and other maternal medical conditions. Therefore, postmortem, placental examination, cytogenetic analysis and fetal maternal hemorrhage testing (at time of induction) should be offered in all stillbirths. Further sequential testing is indicated based on the results of this basic evaluation as well as the specific clinical circumstances accompanying the stillbirth. In addition, the majority of the excess rate of stillbirth seen in non-Hispanic black women is due to obstetric complications, infection, or both causes combined, with stillbirth often occurring intrapartum and at less than 24 weeks gestation.)

(This paper reviews known and suspected causes of stillbirth including genetic abnormalities, infection, fetomaternal hemorrhage and a variety of medical conditions in the mother. The proportion of stillbirths that have a diagnostic explanation is higher in hospitals that conduct a systematic evaluation. The evidence for recommended diagnostic tests for stillbirth are discussed.)

(In this study, the authors determined how often a perinatal autopsy was able to establish the cause of death. This was based on review of 139 autopsies at a single university hospital. Abnormalities likely to be the cause of death were identified in 94% of cases, making postmortem examination one of the highest yield tests for establishing the causes of stillbirth. The findings at autopsy also altered counseling and recurrent risk in 26% of patients.)

(In this study, the success rate for cytogenetic analysis in cases of stillbirth was assessed. This was a prospective, multisite cohort of patients. Tissue sites tested included fetal blood, biopsies of fascia lata, pericardium, cartilage, or skin, as well as placenta and umbilical cord, or CVS and amniocentesis samples. Success rates for cytogenetic testing were significantly higher for invasive testing (amniocentesis or CVS) after fetal death and before labor [85%] vs. analysis of postmortem tissue samples [28%].)

(In this Cochrane review, the best method of second-trimester abortions was evaluated. Based on two randomized studies included in the analysis, dilation and evacuation was found to be superior to the use of prostaglandin F2α.)

(This was a retrospective chart review of 238 patients diagnosed with stillbirth over a 10-year period. The authors found that in most pregnancies with fetal demise, the fetus and the placenta were delivered within 1 week, with coagulation abnormalities noted in 3.2% of patients. This risk, however, increased, if placental abruption or uterine perforation was present.)

(In this publication, the authors evaluated maternal uterine artery Doppler abnormalities between 22-24 weeks in order to correlate the risk of stillbirth. In review of 30,519 studies of unselected women from across the United Kingdom, abnormal uterine artery Doppler predicted the risk of stillbirth due to placental etiologies versus the unexplained intrauterine fetal deaths. Doppler assessment performed well in predicting stillbirth at earlier gestations [58% less than 32 weeks], but had low sensitivity [7%] for predicting fetal demise at term gestation.)